Design, synthesis, and evaluation of 3, 7-substituted coumarin derivatives as multifunctional Alzheimer's disease agents. (1st January 2021)

• Record Type: Journal Article
• Authors: Mzezewa, Sheunopa C.; Omoruyi, Sylvester I.; Zondagh, Luke S.; Malan, Sarel F.; Ekpo, Okobi E.; Joubert, Jacques
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 36:Number 1(2021)
• Page Start: 1606
• Page End: 1620
• Publication Date: 2021-01-01
• Subjects: Alzheimer's disease -- coumarin -- cholinesterase -- monoamine oxidase -- neuroprotection; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2021.1913137
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: Multitarget directed ligands (MTDLs) are emerging as promising treatment options for Alzheimer's disease (AD). Coumarin derivatives serve as a good starting point for designing MTDLs due to their inherent inhibition of monoamine oxidase (MAO) and cholinesterase enzymes, which are complicit in AD's complex pathophysiology. A preliminary series of 3, 7-substituted coumarin derivatives were synthesised and evaluated for enzyme inhibitory activity, cytotoxicity as well as neuroprotective ability. The results indicated that the compounds are weak cholinesterase inhibitors with five compounds demonstrating relatively potent inhibition and selectivity towards MAO-B with IC50 values between 0.014 and 0.498 hx00B5;µM. Significant neuroprotective effects towards MPP + -compromised SH-SY5Y neuroblastoma cells were also observed, with no inherent cytotoxicity at 10 µM for all compounds. The overall results demonstrated that substitution of the phenylethyloxy moiety at the 7-position imparted superior general activity to the derivatives, with the propargylamine substitution at the 3-position, in particular, displaying the best MAO-B selectivity and neuroprotection.